Molecular Basis for the Dynamic Strength of the Integrin α4β1/VCAM-1 Interaction

By Xiaohui Zhang, S. E. Craig, H. Kirby, M. Humphries, V. Moy. 2004

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Intercellular adhesion mediated by integrin α4β1 and vascular cell adhesion molecule-1 (VCAM-1) plays a crucial role in both the rolling and firm attachment of leukocytes onto the vascular endothelium. Essential to the α4β1/VCAM-1 interaction is its mechanical strength that allows the complex to resist the large shear forces imposed by the bloodstream. Herein we employed single-molecule dynamic force spectroscopy to investigate the dynamic strength of the α4β1/VCAM-1 complex. Our force measurements revealed that the dissociation of the α4β1/VCAM-1 complex involves overcoming at least two activation potential barriers: a steep inner barrier and a more elevated outer barrier. The inner barrier grants the complex the tensile strength to withstand large pulling forces (>50 pN) and was attributed to the ionic interaction between the chelated Mg2+ ion at the N-terminal A-domain of the β1 subunit of α4β1 and the carboxyl group of Asp-40 of VCAM-1 through the use of site-directed mutations. In general, additional mutations within the C-D loop of domain 1 of VCAM-1 suppressed both inner and outer barriers of the α4β1/VCAM-1 complex, while a mutation at Asp-143 of domain 2 of VCAM-1 resulted in the suppression of the outer barrier, but not the inner barrier. In contrast, the outer barrier of α4β1/VCAM-1 complex was stabilized by integrin activation. Together, these findings provide a molecular explanation for the functionally relevant kinetic properties of the α4β1/VCAM-1 interaction.

Subfields: Atomic and Molecular Physics, and Optics, Cell Biology, Immunology and Allergy

View Paper: https://www.semanticscholar.org/paper/3d9233eedaf4eb6c6e98e5ccf4a8cfc5ef8f8290

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